JP2008037778A - Method for producing 3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide compound or a salt thereof - Google Patents

Abstract

（式中、Ｒ¹、Ｒ²、Ｒ³は水素原子又は反応に不活性な有機基を示し、Ｘは水素原子を示す）で表されるβ−ケトアミド−Ｎ−スルホン酸又はその塩と不活性溶剤の混合液と、酸無水物と不活性溶剤の混合液とを環化反応に付した後、さらに加水分解反応に付して、下記式（２）
【化２】

で表される化合物又はその塩を製造する際、（Ａ）環化反応により得られた反応生成物を加水分解後の水層の硫酸濃度が３０重量％以上となるように硫酸水溶液と混合して加水分解し、有機層と水層とを分離する工程、又は（Ｂ）加水分解反応後の有機層を濃度３０重量％以上の硫酸水溶液で洗浄する工程を少なくとも実施する。
【選択図】 なし
PROBLEM TO BE SOLVED: To easily and efficiently obtain a high quality 3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide compound or a salt thereof.
The following formula (1)
[Chemical 1]

(Wherein R ¹ , R ² and R ³ represent a hydrogen atom or an organic group inert to the reaction, and X represents a hydrogen atom) and β-ketoamide-N-sulfonic acid or a salt thereof and After subjecting the mixture of the active solvent and the mixture of the acid anhydride and the inert solvent to the cyclization reaction, the mixture is further subjected to a hydrolysis reaction to obtain the following formula (2)
[Chemical 2]

When the compound represented by the formula (1) or a salt thereof is produced, (A) the reaction product obtained by the cyclization reaction is mixed with an aqueous sulfuric acid solution so that the sulfuric acid concentration in the aqueous layer after hydrolysis is 30% by weight or more. At least a step of separating the organic layer from the aqueous layer, or (B) a step of washing the organic layer after the hydrolysis reaction with an aqueous sulfuric acid solution having a concentration of 30% by weight or more.
[Selection figure] None

Description

  The present invention relates to a 3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide compound useful as a sweetener in the food industry, a raw material thereof, an intermediate raw material of fine chemicals, or the like. It relates to a method for producing the salt.

As a method for producing 3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide compounds and salts thereof, acetoacetamide-N-sulfonic acid or a salt thereof in an inert organic solvent 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one-2,2 by reacting SO ₃ and subjecting it to a cyclization reaction to cyclize, followed by hydrolysis reaction -The method of manufacturing a dioxide or its salt is known (refer patent documents 1-3). In this method, the hydrolysis is performed by mixing the reaction product of the ring closure step and water, and 3,4-dihydro-1,2,3-oxathiazine is obtained from the organic layer obtained by liquid separation after hydrolysis. A -4-one-2,2-dioxide compound is obtained. Patent Document 1 describes that the organic layer obtained by liquid separation after the hydrolysis can be purified by extraction using water or dilute aqueous sulfuric acid. However, when water is used for hydrolysis of the cyclization reaction product, there is a problem that the organic layer obtained by liquid separation after hydrolysis is markedly colored, and the subsequent purification load of the target compound increases. Further, even if the organic layer is subjected to extraction using water or dilute aqueous sulfuric acid, the hue of the organic layer is not improved so much.

Japanese Unexamined Patent Publication No. 62-56481 Japanese Patent Laid-Open No. 62-129277 Japanese Patent Laid-Open No. 2005-26379

  An object of the present invention is to provide a method for easily and efficiently obtaining a high-quality 3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide compound or a salt thereof. .

  As a result of intensive studies to solve the above-mentioned problems, the present inventors mixed a reaction product obtained by the cyclization reaction with a sulfuric acid aqueous solution so that the sulfuric acid concentration in the aqueous layer after hydrolysis is not less than a specific concentration. When the organic layer is separated from the aqueous layer, or the organic layer after the hydrolysis reaction is washed with a sulfuric acid aqueous solution with a specific concentration, the organic solvent solution containing the target compound with a good hue with little color can be easily and efficiently used. The present invention was completed by finding out that it can be obtained well.

（式中、Ｒ¹、Ｒ²は、同一又は異なって、水素原子又は反応に不活性な有機基を示し、Ｒ³は水素原子又は反応に不活性な有機基を示し、Ｘは水素原子を示す）
で表されるβ−ケトアミド−Ｎ−スルホン酸又はその塩を不活性溶剤に溶解又は分散させた混合液と、酸無水物を不活性溶剤に溶解又は分散させた混合液とを環化反応に付した後、さらに加水分解反応に付して、下記式（２）

（式中、Ｒ¹、Ｒ²、Ｒ³は前記に同じ）
で表される３，４−ジヒドロ−１，２，３−オキサチアジン−４−オン−２，２−ジオキサイド化合物又はその塩を製造する方法であって、（Ａ）環化反応により得られた反応生成物を加水分解後の水層の硫酸濃度が３０重量％以上となるように硫酸水溶液と混合して加水分解し、有機層と水層とを分離する工程、及び（Ｂ）加水分解反応後の有機層を濃度３０重量％以上の硫酸水溶液で洗浄する工程からなる群より選択された少なくとも１つの工程を含むことを特徴とする３，４−ジヒドロ−１，２，３−オキサチアジン−４−オン−２，２−ジオキサイド化合物又はその塩の製造法を提供する。 That is, the present invention provides the following formula (1):

Wherein R ¹ and R ² are the same or different and each represents a hydrogen atom or an organic group inert to the reaction, R ³ represents a hydrogen atom or an organic group inert to the reaction, and X represents a hydrogen atom. Show)
A cyclization reaction between a mixed solution obtained by dissolving or dispersing β-ketoamide-N-sulfonic acid or a salt thereof represented by the following formula in an inert solvent and a mixed solution obtained by dissolving or dispersing an acid anhydride in an inert solvent: And then subjected to a hydrolysis reaction to obtain the following formula (2)

(Wherein R ¹ , R ² and R ³ are the same as above)
A method for producing a 3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide compound represented by the formula: or a salt thereof obtained by (A) a cyclization reaction The reaction product is hydrolyzed by mixing with a sulfuric acid aqueous solution so that the sulfuric acid concentration in the aqueous layer after hydrolysis is 30% by weight or more, and (B) the hydrolysis reaction. 3,4-dihydro-1,2,3-oxathiazine-4 characterized in that it comprises at least one step selected from the group consisting of washing the subsequent organic layer with an aqueous sulfuric acid solution having a concentration of 30% by weight or more. A method for producing an on-2,2-dioxide compound or a salt thereof is provided.

  In this production method, the sulfuric acid aqueous solution used for hydrolysis in the step (A) is preferably a sulfuric acid aqueous solution having a concentration of 15 to 50% by weight. The sulfuric acid aqueous solution used in the step (B) is preferably a sulfuric acid aqueous solution having a concentration of 45 to 80% by weight.

  Moreover, it is preferable to use the washing | cleaning liquid obtained after washing | cleaning in a process (B) as the sulfuric acid aqueous solution for hydrolysis in a process (A).

  According to the present invention, hydrolysis of the cyclized product and / or washing of the organic layer after hydrolysis is performed using a sulfuric acid aqueous solution having a specific concentration, so that the hue of the organic solvent solution containing the target compound is improved. Can greatly reduce the purification load.

  In the present invention, a mixed solution in which β-ketoamide-N-sulfonic acid or a salt thereof represented by the formula (1) is dissolved or dispersed in an inert solvent, and an acid anhydride is dissolved or dispersed in an inert solvent. The obtained mixed solution is subjected to a cyclization reaction, and then further subjected to a hydrolysis reaction, and 3,4-dihydro-1,2,3-oxathiazin-4-one-2 represented by the above formula (2). , 2-Dioxide compound or a salt thereof is produced.

In the formula (1), the organic group inactive to the reaction in R ¹ , R ² and R ³ is not particularly limited as long as it is inactive to the reaction, and examples thereof include an alkyl group, an alkenyl group, and an alkynyl group. And a cycloalkyl group, an acyl group, an aralkyl group, and an aryl group. Examples of the alkyl group include linear or branched C _1-10 alkyl groups (for example, C _1-6 alkyl groups such as methyl group, ethyl group, propyl group, butyl group, isobutyl group, tert-butyl group, etc.) ) Is included. The alkenyl group includes a linear or branched C _2-10 alkenyl group (for example, a C _2-5 alkenyl group such as a vinyl group, an allyl group, an isopropenyl group, a 1-butenyl group, a 2-butenyl group). Is included. Alkynyl groups include linear or branched C _2-10 alkynyl groups (eg, C _2-5 alkynyl groups such as ethynyl, propynyl, 1-butynyl, 2-butynyl, etc.). Examples of the cycloalkyl group include C _3-10 cycloalkyl groups (preferably C _4-8 cycloalkyl groups) such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. The acyl group includes a linear or branched C _2-10 aliphatic acyl group (for example, an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, etc.), or a C _7-11 aromatic acyl group ( For example, a benzoyl group, a toluyl group, a naphthoyl group, etc.) are included. The aralkyl group includes a C _6-10 aryl-C _1-4 alkyl group (for example, a benzyl group) and the like, and the aryl group includes a C _6-10 aryl group such as a phenyl group.

The salt of the β-ketoamide-N-sulfonic acid compound represented by the formula (1) includes a salt in which a sulfonic acid group is neutralized with a base (sulfonate), and a case where R ³ is a hydrogen atom. Salts in which the —NH— group in the formula is neutralized with a base are included. Examples of such salts (sulfonic acid salts, —NH— salts) include metal salts, ammonium salts, and organic base salts. Examples of the metal salt include salts of alkali metals (Group 1A metal of periodic table) such as Li, Na and K; salts of alkaline earth metals (Group 2A metal of periodic table) such as Mg, Ca, Sr and Ba; Periodic table group 3B metal salts such as Al and Ga; transition metal (for example, periodic table group 3A metal, periodic table group 4A metal, periodic table group 5A metal, periodic table group 6A metal, and Mn group 7A) Metal, periodic table group 8 metal such as Fe, periodic table group 1B metal such as Cu, Ag, Au, periodic table group 2B metal such as Zn, periodic table group 4B metal, periodic table group 5B metal, etc.) Can be mentioned. Preferred metal salts include salts of 1 to 3 metals, such as salts of alkali metals (Na, K, etc.), salts of alkaline earth metals (Mg, Ca, etc.), Al salts, transfer metals (Mn, Fe). Etc.). In view of economy and safety, alkali metal salts such as Na and K are particularly preferable.

Examples of the organic base include aliphatic amines [primary amines (eg, C _1-10 monoalkylamines such as methylamine and ethylamine) and secondary amines (eg, dimethylamine, ethylmethylamine and the like). Di-C _1-10 alkylamine, etc.), tertiary amine (eg, tri-C _1-10 alkylamine such as trimethylamine, triethylamine, etc.)], alicyclic amine (eg, mono-, di- or tri-C, such as cyclohexylamine) _3-12 cycloalkylamine, etc.), aromatic amines (eg, mono-C _6-10 arylamines such as aniline and dimethylaniline, di-C _6-10 arylamines such as diphenylamine, and tri-C _6-10 such as triphenylamine) Arylamines, aralkylamines such as benzylamine), cyclic amines (for example, piperidine, N-methyl Rupiperijin, morpholine, etc.), nitrogen-containing aromatic heterocyclic compound (e.g., pyridine, quinoline, or their derivatives etc.), and others. Preferred organic bases include aliphatic amines. Further, not only aliphatic but also tertiary amine is preferable.

In the formula (1), R ^{1 to} R ³ can be appropriately combined. For example, R ¹ and R ² are each a hydrogen atom or a C _1-4 alkyl group, and R ³ is a hydrogen atom or C _1- Combinations such as ₄ alkyl groups are preferred. Among them, as the compound represented by the formula (1), acylacetamido-N-sulfonic acid in which R ¹ is a C _1-4 alkyl group and R ² and R ³ are hydrogen atoms is preferable, and in particular, R ¹ is methyl. The group acetoacetamide-N-sulfonic acid is preferred. The salt (sulfonate) of the compound represented by the formula (1) is particularly preferably a salt with a tertiary amine.

In the present invention, the acid anhydride is a cyclizing agent (cyclizing dehydrating agent) of β-ketoamide-N-sulfonic acid represented by the formula (1) or a salt thereof (hereinafter sometimes simply referred to as “substrate”). Etc.). Examples of such acid anhydrides include sulfuric acid, halogenated sulfuric acid (fluorosulfuric acid, chlorosulfuric acid, etc.), pyrophosphoric acid (pyrophosphoric acid; halogenated pyrophosphoric acid such as fluoropyrophosphoric acid), nitric acid, boric acid (orthoboric acid, metaboric acid). Inorganic acids such as acids; sulfonic acids, organic phosphoric acids (C _1-4 alkyl phosphoric acids such as methyl phosphoric acid; phosphoric mono C _1-4 alkyl esters such as phosphoric monomethyl ester, phosphoric monoethyl ester, etc.) And acid anhydrides formed from organic acids such as An acid anhydride is an acid anhydride formed by desorbing water from one molecule of acid, an acid anhydride formed by desorbing water from two or more identical acids, and water desorbing from two or more different acids. Any of acid anhydrides (mixed acid anhydrides) produced in the above manner may be used. The acid anhydrides can be used alone or in combination of two or more. A preferred acid anhydride is an acid anhydride formed from an acid containing sulfuric acid, and sulfuric acid anhydride (SO ₃ ) is particularly preferred.

  The acid anhydride is usually used in a proportion of at least 1 mol (for example, 1 to 20 mol), preferably 1 to 10 mol, particularly preferably about 4 to 8 mol, relative to 1 mol of the substrate.

  The cyclization reaction (such as cyclization dehydration reaction) of β-ketoamide-N-sulfonic acid or a salt thereof represented by the formula (1) is performed in the presence of a solvent. As the reaction solvent, various inorganic or organic solvents inert to the reaction (especially not reacting with an acid anhydride) can be used, but an organic solvent inert to the reaction is usually used. Moreover, as a reaction solvent, a substantially anhydrous solvent is usually used.

  In the present invention, the inert solvent for dissolving or dispersing the β-ketoamide-N-sulfonic acid or its salt represented by the formula (1) and the inert solvent for dissolving or dispersing the acid anhydride may be the same or different. It may be. Examples of the inert solvent include aliphatic hydrocarbons (eg, pentane, hexane, octane), alicyclic hydrocarbons (eg, cyclohexane), aromatic hydrocarbons (eg, benzene, toluene, xylene, ethylbenzene, etc.) ), Halogenated hydrocarbons (haloalkanes such as dichloromethane, dichloroethane, chloroform, trichloroethylene, tetrachloroethylene, and trichlorofluoroethylene), esters (for example, carboxylic acid esters such as methyl acetate, ethyl acetate, butyl acetate, and methyl propionate) , Ketones (eg, aliphatic ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone; cyclic ketones such as cyclohexanone), ethers (eg, diethyl ether, diisopropyl ether) Chain ethers such as 1,2-dimethoxyethane, cellosolve, carbitol, diglyme, diethylene glycol dimethyl ether; aromatic ethers such as anisole, 1,2-dimethoxybenzene, diphenyl ether; cyclic ethers such as tetrahydrofuran, dioxolane, dioxane, etc.) Examples thereof include sulfoxides (for example, dimethyl sulfoxide, sulfolane, 2-methylsulfolane, 3-methylsulfolane, etc.). These solvents may be used alone or in combination of two or more. Preferred solvents include halogenated hydrocarbons, with dichloromethane being particularly preferred.

  The cyclization reaction is preferably carried out continuously using a flow-type continuous reactor. As the flow-type continuous reactor, a tubular reactor or a static mixer is preferably used. In order to improve the performance of the cyclization reaction, the substrate and acid anhydride to be subjected to the reaction are each dissolved or dispersed in the above-mentioned solvent, for example, 10 ° C. or lower (about −100 ° C. to 10 ° C.), preferably −80 It is desirable to cool in advance to -10 ° C, particularly preferably -30 ° C to 10 ° C. The substrate concentration in the substrate-containing mixed solution supplied to the reactor can be appropriately selected within a range that does not impair operability and the like, but is usually 0.1 to 50% by weight, preferably 0.5 to 30% by weight, and more preferably. It is about 1 to 20% by weight (particularly 5 to 15% by weight). The acid anhydride concentration in the acid anhydride-containing mixture supplied to the reactor can also be appropriately selected within a range that does not impair operability and the like, and is usually 0.1 to 50% by weight, preferably 0.5 to 30% by weight. %, More preferably about 5 to 20% by weight.

  The total amount of the reaction solvent can be appropriately selected in consideration of reactivity, operation, etc. Generally, it can be selected from a wide range of about 1 to 1000 parts by weight, preferably 5 to 500 parts per 1 part by weight of the substrate. Part by weight, more preferably about 10 to 100 parts by weight, and particularly preferably about 15 to 50 parts by weight.

  The cyclization reaction is preferably carried out by using a flow-type tubular reactor or a static mixer, which may be provided with a cooling device for cooling from the outside, such as a refrigerant jacket or a cooling tank (refrigerant tank). It is performed by continuously supplying a mixed solution of β-ketoamide-N-sulfonic acid or a salt thereof and an inert solvent, and a mixed solution of an acid anhydride and an inert solvent. The reaction temperature of the cyclization reaction can be appropriately set in consideration of the reaction rate and the like.

  As the tubular reactor, a general stainless steel tube, a lining tube such as glass or Teflon (registered trademark), and the like can be used, but the material is not limited thereto. Further, the inner diameter of the tube used is not particularly limited, but considering the removal of heat generated during the cyclization reaction, the inner diameter is preferably several tens mm or less (for example, about 0.2 to 30 mm), The inner diameter is particularly preferably 10 mm or less (for example, about 0.2 to 10 mm). Furthermore, the length of the tube is set to a length necessary to satisfy the residence time required for the reaction. The residence time is about 0.001 to 60 seconds, preferably 0.01 to 40 seconds, more preferably 0.1 to 10 seconds (particularly 1 to 10 seconds). The residence time (seconds) is a value calculated from the reactor volume (ml) / total feed amount of raw material mixture (ml / second).

  In the tubular reactor, as an apparatus for promoting mixing of β-ketoamide-N-sulfonic acid represented by the formula (1) or a salt thereof and an acid anhydride, a stirring mixer, an ultrasonic type A mixer, or a static mixer such as a static mixer, and a pipe joint (hereinafter may be simply referred to as “premixer”) can be installed at the inlet of the tubular reactor. When a premixer is installed at the inlet of the tubular reactor, the residence time in the premixer is, for example, 0.0005 to 30 seconds, preferably 0.01 to 20 seconds, and more preferably 0.1 to 10 Second (particularly 1 to 10 seconds), and the subsequent residence time in the tubular reactor is, for example, 0.001 to 60 seconds, preferably 0.01 to 40 seconds, more preferably 0.1 to 30 seconds. (Especially 1 to 30 seconds).

  In the present invention, a static mixer such as a static mixer can also be used as the reactor. When a static mixer is used as a reactor, since it has a high heat removal capability, it is possible to use a reactor having a larger inner diameter than the tubular reactor. For example, the inner diameter of the static mixer is about 0.2 to 30 mm, preferably about 0.5 to 20 mm. The type of the static mixer is not particularly limited, but as a typical static mixer, a throughser type static mixer, a Kenix type static mixer, or the like can be used. The residence time when a static mixer is used as the reactor is, for example, 0.001 to 60 seconds, preferably 0.01 to 40 seconds, and more preferably about 0.03 to 10 seconds. Also in this case, a preliminary mixer as described above may be provided at the entrance of the static mixer. In this case, the residence time in the premixer is, for example, about 0.0005 to 30 seconds, preferably about 0.01 to 20 seconds, more preferably about 0.1 to 10 seconds (particularly 1 to 10 seconds). The residence time in the static mixer is, for example, about 0.001 to 60 seconds, preferably about 0.01 to 40 seconds, and more preferably about 0.03 to 10 seconds.

  The number of elements of the static mixer is not particularly limited, but is, for example, 5 or more (about 5 to 25), preferably 10 or more.

  By the cyclization reaction, usually water or a base [when a salt of a compound represented by the formula (1) is used as a substrate, etc.] is eliminated, and 3,4-dihydro represented by the above formula (2). A -1,2,3-oxathiazin-4-one-2,2-dioxide compound is formed. In this case, depending on the type and amount of the acid anhydride used, the 3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide compound represented by the formula (2) and the acid anhydride An adduct with a product may be generated. In this case, 3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-represented by the formula (2) is further subjected to a hydrolysis reaction after the cyclization reaction. Dioxide compounds can be obtained.

  The hydrolysis is performed, for example, by subjecting the reaction liquid obtained by the cyclization reaction to an appropriate treatment as necessary, and then mixing water or a water-containing liquid (for example, an aqueous sulfuric acid solution). Hydrolysis may be performed by any method such as a continuous method, a batch method, and a semi-batch method. In the case of continuous hydrolysis, in addition to using a stirring tank, a continuous processing apparatus used for the cyclization reaction can also be used. The temperature of the water or water-containing liquid to be subjected to the hydrolysis reaction and the reaction temperature are, for example, 0 to 50 ° C., preferably 10 to 40 ° C. The amount of water (or water contained in the water-containing liquid) is, for example, 1 to 100 mol, preferably 1 to 50 mol, more preferably 2 to 20 mol, per 1 mol of the acid anhydride used for the cyclization reaction. Degree. A large excess of water may be used. The reaction time of the hydrolysis reaction (residence time in the case of a continuous type) is, for example, within 1 hour (about 0.1 minute to 1 hour), preferably about 1 to 10 minutes.

  The 3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide compound represented by the formula (2) thus obtained is washed, separated, concentrated, for example. Can be separated and purified by separation means such as solvent exchange, extraction, crystallization, recrystallization and column chromatography. For example, after separating the reaction liquid after completion of hydrolysis into an organic layer (inert solvent layer) containing the target compound and an aqueous layer, and washing the organic layer with water or a water-containing liquid (for example, an aqueous sulfuric acid solution), The target compound can be isolated by performing operations such as concentration, solvent exchange, and crystallization. In addition, in the water layer, a solvent incompatible with water (or immiscible) [solvent used in the cyclization reaction, ester of organic mono- or dicarboxylic acid (esters exemplified in the section of the reaction solvent, etc.), etc. The target compound remaining in the aqueous layer can be extracted and recovered.

  An important feature of the production method of the present invention is that in the step after the cyclization reaction, (A) the sulfuric acid concentration in the aqueous layer after hydrolysis of the reaction product obtained by the cyclization reaction is 30% by weight or more. From the group consisting of a step of mixing with an aqueous sulfuric acid solution for hydrolysis to separate the organic layer from the aqueous layer, and (B) a step of washing the organic layer after the hydrolysis reaction with an aqueous sulfuric acid solution having a concentration of 30% by weight or more. It includes at least one selected step. When the step (A) is performed, when the reaction mixture after hydrolysis is separated into an organic layer (including the target compound) and an aqueous layer, the reaction mixture is separated neatly, and impurities (colored substances, etc.) are added to the organic layer. Migration and distribution are suppressed, and an organic layer (a target compound-containing solution) having a good hue (low coloring degree) and a low impurity content can be obtained. In addition, when the step (B) is performed, impurities (colored substances and the like) contained in the organic layer move to an aqueous layer made of an aqueous sulfuric acid solution, and the hue and impurity content of the organic layer are greatly improved. Therefore, by carrying out step (A) and / or step (B), the subsequent purification step can be simplified, the purification load can be reduced, and thus a high-quality target compound can be obtained easily and efficiently. . More specifically, the coloring component resulting from the cyclization reaction and hydrolysis has a feature that it is difficult to remove even if a subsequent purification step, for example, crystallization operation or activated carbon treatment is performed. In general, the compound represented by the formula (2) is derived from its salt. However, if the compound represented by the formula (2) contains a coloring component, it is also decolorized in the purification step of the salt. Therefore, the crystallization operation must be performed several times. Furthermore, when performing the crystallization operation as the purification of the salt, the product loss in the filtrate is large and the yield is reduced. Therefore, the reuse of the filtrate is indispensable in the salt production process. Since the hue of the salt crystallization filtrate is remarkably deteriorated, it is difficult to reuse. According to the production method of the present invention, since the coloring component can be efficiently removed, the crystallization operation of the salt of the compound represented by the following formula (2) can be reduced, for example, once or twice, and the purification process is simplified. it can. Moreover, the filtrate produced by the crystallization operation can be reused, and the yield is improved.

  The manufacturing method of this invention should just contain at least one process among a process (A) and a process (B). For example, when performing the step (A), it is not always necessary to wash the organic layer after the hydrolysis reaction with a sulfuric acid aqueous solution having a concentration of 30% by weight or more, for example, water or a sulfuric acid aqueous solution having a concentration of less than 30% by weight. Etc. may be used for cleaning, and the cleaning operation may be omitted. In addition, when performing the step (B), hydrolysis of the reaction product obtained by the cyclization reaction is mixed with an aqueous sulfuric acid solution so that the sulfuric acid concentration in the aqueous layer after hydrolysis is not less than 30% by weight. For example, the hydrolysis may be performed using water. However, in order to obtain a higher-quality target compound more easily and efficiently, it is preferable to carry out both step (A) and step (B).

  In the step (A), the sulfuric acid concentration in the aqueous layer after hydrolysis may be 30% by weight or more (for example, 30 to 80% by weight), preferably 35 to 75% by weight, more preferably 40 to 70% by weight. %, More preferably 45 to 70% by weight. If the sulfuric acid concentration in the aqueous layer after hydrolysis is too low, the hue of the organic layer obtained by liquid separation tends to deteriorate and the liquid separation property also tends to deteriorate. On the other hand, if the sulfuric acid concentration in the aqueous layer after hydrolysis is too high, the organic layer after separation may become cloudy or the liquid separation property may be reduced. The concentration of the sulfuric acid aqueous solution used for the hydrolysis is preferably 15 to 50% by weight, more preferably 20 to 45% by weight, and particularly preferably about 20 to 40% by weight. When the concentration of the sulfuric acid aqueous solution used for the hydrolysis is too low, the hue of the organic layer to be obtained tends to deteriorate and the liquid separation property also tends to decrease. On the other hand, if the concentration of the sulfuric acid aqueous solution used for the hydrolysis is too high, the organic layer may become cloudy, the liquid separation property may decrease, or the distribution ratio of the target compound to the organic layer may decrease. The amount of the sulfuric acid aqueous solution used for the hydrolysis may be an amount that contains an amount of water necessary for the hydrolysis and the concentration of sulfuric acid after the hydrolysis is in the above range. For example, the amount of the sulfuric acid aqueous solution used for the hydrolysis varies depending on the type and amount of the acid anhydride, but generally 80 to 400 parts by weight, preferably 100 parts by weight of the acid anhydride is used. About 100 to 300 parts by weight.

  In the step (B), the concentration of the sulfuric acid aqueous solution used for washing the organic layer after the hydrolysis reaction may be 30% by weight or more (for example, 30 to 80% by weight), but preferably 45 to 80% by weight. Preferably it is 50 to 80 weight%, More preferably, it is 60 to 78 weight%. If the concentration of the aqueous sulfuric acid solution used for the washing is too low, the effect of improving the hue of the organic layer is small, and the liquid separation property tends to decrease. On the other hand, if the concentration of the sulfuric acid aqueous solution used for the washing is too high, the organic layer may become cloudy or the liquid separation property may be lowered. The amount of the sulfuric acid aqueous solution used for the washing is, for example, about 1 to 100 parts by weight, preferably about 2 to 50 parts by weight with respect to 100 parts by weight of the organic layer used for washing. From the washed organic layer, the target compound with good quality can be obtained by performing operations such as concentration, solvent exchange, and crystallization as described above.

  The washing liquid after washing in the step (B) can be used as it is, or appropriately diluted or concentrated and used as the sulfuric acid aqueous solution for hydrolysis in the step (A). By using the cleaning solution as an aqueous sulfuric acid solution for hydrolysis, the amount of waste treated and discarded can be greatly reduced, and the compound represented by the formula (2) contained in the cleaning solution can be recovered. can do.

In addition, the salt of the 3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide compound represented by the formula (2) is a compound (R) represented by the formula (2). ^The compound in which ³ is a hydrogen atom can be obtained by subjecting it to a conventional salt formation reaction such as reaction with a base. Examples of the salt of the 3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide compound represented by the formula (2) include metal salts, ammonium salts, and organic base salts. It is done. The kind of metal salt, the kind of organic base, and preferred examples are the same as in the case of the salt of the β-ketoamide-N-sulfonic acid compound represented by the formula (1). Particularly preferred salts are alkali metal salts such as sodium salt and potassium salt.

The alkali metal salt of the 3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide compound represented by the formula (2) is a compound represented by the formula (2) (R ³ is a hydrogen atom), for example, alkali metal hydroxide (sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonate (sodium carbonate, potassium carbonate, etc.), alkali metal bicarbonate (sodium bicarbonate) And a base containing an alkali metal such as potassium hydrogen carbonate).

  The salt of the 3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide compound represented by the formula (2) is, for example, concentrated, extracted, crystallized, recrystallized, column Separation and purification can be performed by separation means such as chromatography.

As a representative example of the 3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide compound represented by the formula (2) or a salt thereof, 6-methyl-3,4 -Dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide, 6-ethyl-3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide 6-n-propyl-3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide, 6-i-propyl-3,4-dihydro-1,2,3- 6-C _1-4 alkyl-3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxides such as oxathiazin-4-one-2,2-dioxide; 6-phenyl -3,4-dihydro-1,2,3-oxathiazine-4 6-aryl-3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxides such as -on-2,2-dioxide; 5-methyl-6-methyl-3, 4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide, 5-methyl-6-ethyl-3,4-dihydro-1,2,3-oxathiazin-4-one 5,6-diC _1-4 alkyl-3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide such as 2,2-dioxide; 5-phenyl-6 5-aryl-6-C _1-4 alkyl-3,4-dihydro-1,2, such as methyl-3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide 3-oxathiazin-4-one-2,2-dioxide; 5-methi 6-phenyl-3,4-dihydro-1,2,3-oxathiazin-4-one--2,2-5-C _1-4 alkyl such as-dioxide-6-aryl-3,4-dihydro-1 , 2,3-oxathiazin-4-one-2,2-dioxide; 6-cyclopentyl-3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide, 6-cyclohexyl 6-C _3-8 cycloalkyl-3,4-dihydro-1,2,3-oxathiazine such as 3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide 4-one-2,2-dioxide; 5-cyclopentyl-6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide, 5-cyclohexyl-6 Methyl-3,4-dihi B-1,2,3-like oxathiazine-4-one 2,2-dioxide 5-C _3-8 cycloalkyl -6-C _1-4 alkyl-3,4-dihydro-1,2,3 -Oxathiazin-4-one-2,2-dioxide; 5-methyl-6-cyclopentyl-3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide, 5-methyl 5-C _1-4 alkyl-6-C _3-8 cycloalkyl-3, such as -6-cyclohexyl-3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide, 4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide; 6-vinyl-3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide 6-C _2-4 alkenyl-3,4-dihydro- 6 such as 1,2,3-oxathiazin-4-one-2,2-dioxide; 6-acetyl-3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide -C _2-6 acyl-3,4-dihydro-1,2,3-oxathiazine-4-one 2,2-dioxide, and their salts.

In particular, a 3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide compound (for example, 6-methyl-3,4) in which R ¹ is a methyl group in the formula (2). -Dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide, etc.) are part of their physiologically acceptable salts (for example, salts with Na, K, Ca, etc.). It is preferable because it is used as a sweetener in the food industry. Among them, a salt with potassium is particularly useful as acesulfame (acesulfame K).

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

Example 1
The reaction was carried out using a stainless steel tube with an inner diameter of 4 mm and an effective length of 2 m equipped with a Kenix type static mixer with an inner diameter of 3.4 mm, a length of 10 cm and 17 elements as a raw material mixer (preliminary mixer). did. 0.47 mol of acetoacetamide-N-sulfonic acid triethylammonium was dissolved in 1885 g of dichloromethane and cooled to -10 ° C. Further, 2.70 mmol of anhydrous sulfuric acid was dissolved in 1784 g of dichloromethane, and the solution was similarly cooled to −10 ° C. Into the reactor immersed in a refrigerant at −30 ° C., a triethylammonium acetoacetamide-N-sulfonate solution was continuously injected at a rate of 201 g / min and an anhydrous sulfuric acid solution at a rate of 200 g / min for 10 minutes. The residence time was 5.1 seconds. The reaction solution was continuously withdrawn into a 2 L separable flask while stirring at 500 rpm, and a 40 wt% sulfuric acid aqueous solution was simultaneously supplied at a rate of 37 g / min for hydrolysis. A hydrolysis reaction was performed at 15 to 25 ° C., and the reaction solution was continuously withdrawn and allowed to stand to separate a dichloromethane layer and an aqueous layer. The sulfuric acid concentration in the aqueous layer was 52% by weight. When the absorbance analysis at 344 nm of the dichloromethane layer was performed, the absorbance was 0.531. As a result of quantifying 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide contained in the dichloromethane layer by HPLC, the yield (acetoacetamido-N -Based on triethylammonium sulfonate) was 70%.

Example 2
The reaction was carried out using a stainless steel tube with an inner diameter of 4 mm and an effective length of 2 m equipped with a Kenix type static mixer with an inner diameter of 3.4 mm, a length of 10 cm and 17 elements as a raw material mixer (preliminary mixer). did. 0.47 mol of acetoacetamide-N-sulfonic acid triethylammonium was dissolved in 1885 g of dichloromethane and cooled to -10 ° C. Further, 2.70 mmol of anhydrous sulfuric acid was dissolved in 1784 g of dichloromethane, and the solution was similarly cooled to −10 ° C. Into the reactor immersed in a refrigerant at −30 ° C., a triethylammonium acetoacetamide-N-sulfonate solution was continuously injected at a rate of 201 g / min and an anhydrous sulfuric acid solution at a rate of 200 g / min for 10 minutes. The residence time was 5.1 seconds. The reaction solution was continuously withdrawn into a 2 L separable flask while stirring at 500 rpm, and a 40 wt% sulfuric acid aqueous solution was simultaneously supplied at a rate of 37 g / min for hydrolysis. A hydrolysis reaction was performed at 15 to 25 ° C., and the reaction solution was continuously withdrawn and allowed to stand to separate a dichloromethane layer and an aqueous layer. The sulfuric acid concentration in the aqueous layer was 52% by weight. A 75 wt% aqueous sulfuric acid solution was added to the extracted dichloromethane layer at a ratio of 0.05 part by weight to 1 part by weight of the dichloromethane layer, and the mixture was sufficiently stirred. After stirring, the mixture was allowed to stand for liquid separation. When the obtained organic layer (dichloromethane layer) was subjected to absorbance analysis at 344 nm, the absorbance was 0.261. In addition, as a result of quantifying 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide contained in the organic layer (dichloromethane layer) by HPLC, the yield ( Acetoacetamide-N-sulfonic acid triethylammonium standard) was 65%.
In the washing step, the yield is reduced by 5%, but the washing solution after washing (sulfuric acid aqueous solution layer) can be used as a part of the sulfuric acid aqueous solution for hydrolysis in the hydrolysis step, and therefore included in the washing solution. The total amount of methyl-3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide can be recovered.

Comparative Example 1
The reaction was carried out using a stainless steel tube with an inner diameter of 4 mm and an effective length of 2 m equipped with a Kenix type static mixer with an inner diameter of 3.4 mm, a length of 10 cm and 17 elements as a raw material mixer (preliminary mixer). did. 0.82 mol of acetoacetamide-N-sulfonic acid triethylammonium was dissolved in 3390 g of dichloromethane and cooled to −10 ° C. Further, 4.90 mmol of sulfuric anhydride was dissolved in 3241 g of dichloromethane, and the solution was similarly cooled to −10 ° C. The acetoacetamide-N-sulfonic acid triethylammonium solution was continuously injected at a rate of 362 g / min and an anhydrous sulfuric acid solution at a rate of 363 g / min for 10 minutes into the reactor immersed in a refrigerant at −30 ° C. The residence time was 2.8 seconds. The reaction solution was continuously withdrawn into a 2 L separable flask while stirring at 500 rpm, and water for hydrolysis was simultaneously supplied at a rate of 100 g / min. A hydrolysis reaction was performed at 15 to 25 ° C., and the reaction solution was continuously withdrawn and allowed to stand to separate a dichloromethane layer and an aqueous layer. The sulfuric acid concentration in the aqueous layer was 26% by weight. When the absorbance analysis at 344 nm of the dichloromethane layer was performed, the absorbance was 0.845. As a result of quantifying 6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide contained in the dichloromethane layer by HPLC, the yield (acetoacetamido-N -Based on triethylammonium sulfonate) was 70%.

Claims (4)

Following formula (1)

Wherein R ¹ and R ² are the same or different and each represents a hydrogen atom or an organic group inert to the reaction, R ³ represents a hydrogen atom or an organic group inert to the reaction, and X represents a hydrogen atom. Show)
A cyclization reaction between a mixed solution obtained by dissolving or dispersing β-ketoamide-N-sulfonic acid or a salt thereof represented by the following formula in an inert solvent and a mixed solution obtained by dissolving or dispersing an acid anhydride in an inert solvent: And then subjected to a hydrolysis reaction to obtain the following formula (2)

(Wherein R ¹ , R ² and R ³ are the same as above)
A method for producing a 3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide compound represented by the formula: or a salt thereof obtained by (A) a cyclization reaction The reaction product is hydrolyzed by mixing with a sulfuric acid aqueous solution so that the sulfuric acid concentration in the aqueous layer after hydrolysis is 30% by weight or more, and (B) the hydrolysis reaction. 3,4-dihydro-1,2,3-oxathiazine-4 characterized in that it comprises at least one step selected from the group consisting of washing the subsequent organic layer with an aqueous sulfuric acid solution having a concentration of 30% by weight or more. -Manufacturing method of ON-2,2-dioxide compound or its salt.   The 3,4-dihydro-1,2,3-oxathiazin-4-one-2,2- of claim 1, wherein the sulfuric acid aqueous solution used for hydrolysis in the step (A) is a sulfuric acid aqueous solution having a concentration of 15 to 50% by weight. A method for producing a dioxide compound or a salt thereof.   The 3,4-dihydro-1,2,3-oxathiazin-4-one-2,2-dioxide compound according to claim 1, wherein the sulfuric acid aqueous solution used in step (B) is a sulfuric acid aqueous solution having a concentration of 45 to 80% by weight. Or the manufacturing method of the salt. The 3,4-dihydro-1,2,3-oxathiazin-4-one-2 according to claim 1 or 3, wherein the washing liquid obtained after washing in the step (B) is used as a sulfuric acid aqueous solution for hydrolysis in the step (A). , 2-Dioxide compound or a salt thereof.